Process for the preparation of 5alpha, 6alpha-difluoro steroids



3,097,199 PROCESS FDR THE PREPARATION OF 5096a- DIFLUORO STEROIDS Albert Bowers, Mexico City, Mexico, assignor, by mesne assignments, to Syntex Corporation, a corporation .of Panama No Drawing. Filed Jan. 19, 1961, Ser. No. 83,630 Claims priority, appiication Mexico Jan. 19, 1960 26 Claims. (Cl. 260-235-55) ing 50t,6ot-dlflll0l'0 derivatives which are formed by the reaction of a A -steroid with a fluorinating agent. The present invention also relates to the novel 5u,6a-difluoro derivatives which are valuable fhOIHlOIIBS as hereinafter are more fully described.

The production of oa-fluoro-A -3-keto-steroids from A -3-keto compounds by prior methods has certain disadvantages. Thus, the known procedures involve shifting the C-4,5 double bond to 06,6 as by formation of the 3-cycloethyleneketal of the starting compound, formation of the 5,6-oxido-derivatives, separation of the 50:,604- epoxides from the Sport-isomer, opening of the 50;,611- oxido derivative with hydrogen fluoride or boron trifluoride etherate, regenerating the 3-keto group, dehydration at 04,5 to form the 04,5 double bond and inversion of the steric configuration at C-6.

In accordance with the present method, a A -3fi-hydroxy compound is treated with hydrogen fluoride and a metallic compound to directly form a 5a, 6oc-diflll0r0 compound, the 3 8-hydroxy group is converted to the 3-keto group and the latter is treated with an acid or base to afiord the 6u-fluoro-A' -3-keto compound. It is apparent the present method of introducing a fluorine atom at -6 involves fewer steps as compared to the known procedures and hence can be generally achieved at higher yields and lower cost. There has been further provided therefore a novel process involving novel intermediates which per se are useful and valuable hormones.

The novel method of the present invention isiHustrated by the following equation insofar as rings A and B are concerned I i HO-- HO i (IV) (III) In practicing the processoutlined above a A -3fl-hydroxy steroid (I) dissolved in an inert organic solvent such as methylene dichloride, dioxane or carbon tetrachloride, is added to a mixture of anhydrous hydrogen fluoride and a metallic reagent such as lead tetraacetate,

Patent 0 lead dioxide, cobaltic oxide or osmium tetroxide at about 3,097,199 Patented July 9, 1963 ice 8'0 C. to form ,the 3fi-l1yd10Xy-5oc,6ocdifillOIO compound (II). The cis addition of fluorine to the C-5, 6 double bond is preferably effected with lead tetraacetate or lead dioxide and hydrogen fluoride and the reaction mixture is stirred at "C. for a period of time in the order of 15 minutes. However the reaction may also be conducted for a longer period of time such as for example for one hour at a temperature ranging from --80 C. to -10 C. The thus formed 3fi-hydroxy-5a,6u-difluoro compound (II) is oxidized with 8 N chromic acid or chromium trioxide-pyridine complex to afford the corresponding 3-keto-5a,6a-difluoro compound (III) with concomitant oxidation of ll-hydroxy groups, if present, to the ll-keto group. Upon treatment of the latter compound with an acid or a base, preferably by refluxing with sodium acetate in methanol, there is formed the 6a-fluoro-A -3-keto compound (IV).

The starting compounds which are particularly suitable for the novel reaction to give useful products are illustrated by the following formulas:

CHaR 41:0 -32 MN Ra onion Homg ii...

In the above formulas R and R represent hydrogen or methyl; R and R represent hydrogen, hydroxyl or ,an acyloxy group of a hydrocarbon carboxylic acid of less than 12 carbon atoms; R R and R represent hydrogen or the acyl group of a hydrocarbon carboxylic acid and R and R jointly with the oxygen function may represent the grouping:

carbon atoms such as methyl, ethyl, propyl, vinyl, butenyl,

ethinyl, propinyl and bu-tinyl. The starting compounds may also contain a halogen atom such as chlorine, fluorine or bromine at C-9a.

The novel process therefore leads to the production of the novel a,6u-difluoro compounds of the following In the above formulas, Y, A, R, R through R have the same meaning as heretofore set forth and Z represents keto or fi-hydroxy.

In addition to being valuable as intermediates for the preparation of the important a-fluoro compounds, the above compounds are also valuable hormones. Thus com pounds of type A are valuable androgenic-type hormones having a favorable anabolic-androgenic ratio; compounds -dione; 16(u or [3)-methyl-pregnan-3fl-ol-20-one and 16(a or B)methyl-pregnane-3,20-dione; 16(oc or ,8)methylpregnane-3,8,l1a-dio1-20-one and 16(1): or 8)-methylpregnane-3,ll,20-trione; 16(a or ,B)-methyl-l7u-acyloxypregnan-3fl-ol-20-one and 16(0: or fl)-methyl-17a-acyloxypregnane-3,20-dione; 16(oc or fi)-methyl-17a-acyloxypregnane-3/3,1la-diol-20-one and 16(a or B)-methyl-l7uvacyloxy-pregnane-3 l 1,20-trione; l7ot-acyloxy-pregnane- 3,B,1la-diol-20-one and l7a-acyloxy-pregnane-3,l1,20-trione; the ZI-acetate of pregnane-3,8,11a,17a,2l-tetrol-20- one and of pregnan-17a-ol-3,l1,20-trione; the Zl-acetate of pregnane-3B,17o,21-trio1-20-one and of pregnane-17a, 21-diol-3,20-dione; the 2l-acetate of the l6,l7-acetonide of pregnane-Zifl,16u,17oc,21-tetrol-20-one and of pregnanel6a,l7a,2l-triol-3,20-dione.

Although 3B-hydroxy-A -steroids are preferred starting materials it is apparent other 3-oxygenated A -steroids are of type B are potent progestational agents which exhibit anti-estrogenic activity and compounds of type C are pituitary inhibitors in addition to exhibiting anti-estrogenic and anti-gonadotrophic activity.

Typical compounds within the above definitions which may be subjected to the novel reaction are A -androsten- 3B-ol-l7-one, A -androstene-3/3,l7fi-diol, 17a-methyl-A androstene-3/3, 17,6-diol, 17a-ethyl-A -androstene-3fl, 17,3- diol, 17a-ethinyl-A -androstene-3,8,l7fi-diol, the l9-norderivatives thereof, A -pregnene-3 3-ol-20-one, the 17- -acylates of A -pregnene-3B,17a-diol-20-one, 16(a or ,8)- methyl-A -pregnen-3fi-ol-20-one, 16(a or 8)-methyl-A pregnene-3;3,11u-diol-20-one, the 17-acylates of 16(a or fi)-methy-l-A -pregnen-3 [3,17 a-diol-ZO-one, the 17-acylates of 16(oc or fl)-methyl-A -pregnen-3[3,11a,l7a-triol-2O- one, the 17-acylates of A -pregnene-3B,1la,17a-triol-20- one, the 2l-acetate of A -pregnene-3fl,1la,l7a,21-tetrol-20- one, the 2l-acetate of A -pregnene-3 3,l7u,2l-triol-20-one,

the 21-acetate of the 16,17-acetonide of A -p1'egnen-3/3,

161x,17a,21-tetrol-20-one.

There are thus prepared by the novel method of the present invention the corresponding 5u,6a-difluoro derivatives of androstan-3 3-ol-17-one, androstane-3fl,17fi-diol, 17a-methyl-androstane-3 3,17,3-diol, 17a-ethyl-androstane- 3;8,17,8-di01, 17u-ethiny1-androstane-3/8,17p-diol, the 19-nor derivatives thereof, pregnan-3 8-ol-20-one, the l7-acylates of pregnane-Sfl,l7a-diol-20-one and of pregnar1-17a-ol-3, of 16(a or fi)-methyl-A -pregnen-3fl,11a,17a-trio1-20- suitable in the novel reaction. Thus, Bfi-acylates, 3-enol esters, 3-enol ethers and 3-cyclic alkylene ketals may also serve as starting compounds for the preparation of the 50:,6a-difluoro-derivatives.

The following specific examples serve to illustrate but are not intended to limit the scope of the invention.

Example I A solution of 5 g. of A -pregnen-3p-ol-20-one in ml. of methylene chloride was added with stirring over 15 minutes to a mixture of 10 g. of lead tetraacetate and 20 ml. of anhydrous hydrogen fluoride, cooled in acetone- Dry Ice bath to -80; the mixture was then stirred at 80 for 15 minutes and at the end of this time cautiously poured into an aqueous ice-cold solution of sodium carbonate, containing an excess of sodium carbonate. The organic phase was separated, the aqueous phase extracted with methylene chloride and the methylene solutions were combined, washed with water until neutral, dried over anhydrous sodium sulfate and evaporated to dryness. Subsequent chromatography on neutral alumina afforded 5a, 60:, difluoro pregnan 3e ol 20= one, M.P. 22l- 223 [a] +88 (CHCl This compound exhibited anti-estrogenic activity.

An ice-cold solution of 5 g. of the foregoing compound, in 250 ml. of acetone, was treated with an excess of 8 N chromic acid, with stirring. The 8 N chromic acid was prepared in aqueous dilute sulfuric acid. The temperature was maintained at 0 during the addition. Stirring was then continued for 2 minutes, addition of ice-water gave a precipitate which was water-washed, dried and crystallized from acetone-hexane to aflord 5a,6u-difluoropregnane-3,20-dione, M.P. 224226, [a] +78 (CHClg).

A mixture of 5 g. of the foregoing compound, 5 g. of sodium acetate and ml. of methanol was refluxed for 2 hours, then chilled, diluted with water and the solid collected by filtration, water-washed, dried and crystallized from acetone-hexane, furnishing 6u-fluoro-progesterone.

Example 11 Example III The fluorinating procedure of Example I was repeated but using lead dioxide instead of lead tetraacetate. 5a, 6zx-difluoro-pregnan-3/3-ol-20-one was obtained, identical with the compound prepared by the use of lead tetraacetate.

i i 1 l l l l Example IV A mixture of '1 g. of A -pregnene-3B,l7a-diol-20eone [Ringold et al., J. Am. Chem. Soc., 78, 820 (1956)], 50ml. of dry benzene, 2 ml. of propionic anhydride and 0.5 g. of p-toluenesulfonic acid monohydrate was left at room temperature overnight, then water-washed, dried over anhydrous sodium sulfate and evaporatedto dryness. The residue was treated with 50 ml. of 1% methanolic potassium hydroxide, under an atmosphere of nitrogen, at 5 ,for 2rhours. Afteracidifying with acetic acid, the volume wasreduced to about 20 ml. in vacuo. Water was then added, the precipitate collected by filtration, water-washed, dried and crystallized from acetonehexane. Thus A -pregnene-3/3,17a-diol-20-one 17-propionate was obtained which in its turn, was submitted to the reaction described in Example I. There were produced, consecutively: S a,6a-difluoropregnane-3 B,17oc-di01 20-one 17-pr0pionate and 5a,6o-difluoropregnan-17a-ol- 3,20-dione propionate which exhibited anti-ovulation activity; the latter compound was converted into 6u-fiuoro- 17a-hydroXy-progesterone prop-ionate as described above.

Example V Example VI To a solution of 10 g. of 16-methyl-A pregnadien- 3,8-01-20-one [(Romo et al., Bol. inst. Quirn. Mex, 4, .125 (1952)] in 700 ml. of methanol were added 20' n11.

of 4 N aqueous sodium hydroxide and then 40 of 30% aqueous hydrogen peroxide, while stirring and maintaining the temperature below C. The mixture was left in the refrigerator overnight, then poured into 2750 ml. of ice-water, the solid was collected by filtration, water-washed and dried, affording 16-rnethyl-l6a,l7aoxido-M-pregnen-Iafl-ol-ZO-one. 10 g. of this compound were suspended in .100 ml. of methylene chloride, the

suspension was chilled to 10 C. and 10 ml. of acetic acid, saturated with dry hydrogen bromide, were added, little by little, while stirring and at 15 C. The mixture was then stirred at room temperature for half an hour, at the end of this timeit was diluted with ice-water, the organic .layer was separated, water-washed, dried over anhydrous sodium sulfate and evaporated to dryness, under reduced pressure.

5 g. of the thus obtained bromohydrin were then refluxed with 10 g. of Raney nickel and 150 ml. of

methanol under an atmosphere of nitrogen for 4 hours. .At the end of this time, the solid was filtered and the filtrate was concentrated to the point of crystallization. After cooling, the product was collected by filtration,

water-washed, driedand chromatographed on silica gel furnishing 16a-methy1-A -pregnene-3 [3,17a-di0h20-one.

The foregoing compound wasdivided into 5 portions of 1 g. each; 1 g. was submitted to the reactions described in Example I withoutesterification of the 17a-hydroxy group; the other portions were first converted into the 17-acetate, -17-p-ropionate, l7-caproate and 17-cy'clo- .pe'ntylpropionate, respectively of l6a-methyl-A -pregnene- 3,8,17a-diol-20-one by the method described in Example ,IV and were then subjected to the reactions described in Example I. Thus consecutively were obtained: 5a,6a-

difluoro-16u-methyl-pregnane-3/3,17a-diol-20-one, 5a,6udifluoro-l6a-methyl-pregnan-17fi-ol 3,20 dione and 60afluoro-l6a-methyl l7a-hydroxyprogesterone and the 17- 6 acetates, 17-propionates, 17-caproates and 17-cycl opentylpropionates, respectively, of said compounds. 50,6a-difluoro-l6u-methylpregnan-l75-01-320 dione l7-acetate exhibited progestational activity.

Example VII A mixture of 10 g. of A -pregnadiene-3fi,1la-diol ZO-one ['Halpern and Djerassi; J. Am. Chem. Soc., 81, 439 (1959)], 400 ml. of dry benzene and 5 ml. of 3 N ethereal methylmagnesium bromide was refluxed for 6 hours. At the end of this time the mixture was poured into 1 liter of ice-water containing 40 g. of ammonium chloride, the organic layer was separated, the aqueous phase was extracted with ethyl acetate and the solutions in the organic solvents were cooled, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and evaporated to dryness. Subsequent chromatography, on neutral alumina, furnished [16amethyl-A -pregnene-3p, 1 la-diol-ZO-one.

The foregoing compound was submitted to the reactions described in Example I, and thus were obtained, consecutively: 16cc methyl-5a,6 p-dlfluoro-pregnane-3 8,11adiol-ZO-one; 16a-methyl-5a,6u-difiuoro-pregnane-3,11,20- trione; and 6a-fluoro-16a-methyl-1l-keto-progesterone.

Example VIII 8 g. of 16a-methyl-A -pregnene6fi,lla-diol 2o one, in 30 ml. of pyridine was treated with 8 m1. of acetic anhydride, at room temperature overnight. The mixture was then poured into water; after heating on the steam bath for half an hour and subsequent cooling, the solid was isolated from the liquid by filtration, water-washed, dried and crystallized from acetone-hexane, furnishing 16a-methyl-A pregnene-3B,1 1a-diol-20-one diacetate.

8 g. of the foregoing compound were dissolved in ml. of chloroform containing a few drops of pyridine, the solution was chilled to 0 C., and then little by little and with stirring, 1.05 molecular equivalents of chlorine dissolved in chloroform were added, The mixture was left at room temperature for about 1 hour, then the excess of chlorine was eliminated by passing through the mixture a current of dry air. Subsequently it was washed with aqueous sodium bicarbonate, dried over anhydrous sodium sulfate and evaporated to dryness. The residue crystallized from ethanolbenzene, affording the di-acetate of 16a methyl 5a,6/3-dichloropregnane-3fl,lla-diol-ZO- one. 7

From a mixture of 8 g. of the foregoing compound, 3.6 g. of p-toluenesulfonic acid monohydrate and 400ml. of acetic anhydride, there were distilled 320 ml. in the course of 15 hours. The residue was cooled and poured into ice-water, the product was then extracted with ether and the extract was washed consecutively with 5% aqueous sodium bicarbonate and water, then dried over anhydrous sodium sulfate. Finally, the ether was ev aporated and methyl 5a,6,8 dlichlono-A -pregnene- 3a,1loz,2.O-Ti0i triacetate was obtained.

A mixture of 4 g. of the foregoing compound and 1.2 molecular equivalents of perbenzoic acid in 160 ml. of benzene was left at room temperature overnight, then diluted with Water and the organic l ayer was separated, washed consecutively with aqueous sodium bicarbonate and with water, dried over anhydrous sodium'sulfateend finally evaporated to dryness, yielding IGovmothYI-Safiadichloro -17 ,20-oxido-pregnane-3B,11a,20-triol tniacetate.

The foregoing compound was reacted with 2 liters of 0.5 N sodium hydroxide solution (prepared in equal parts of ethanol and Water), at room temperature tand'for 24 hours. The mixture was then acidified-with acetic acid 180 ml. of 80% acetic acid, at 40 C., maintaining this temperature and while stirring 1.8 g. of zinc dust were added. Stirring was continued at 40 C. for 16 hours, the solid filtered, then water was added to the filtrate and the product extracted with chloroform. The extract was washed consecutively with aqueous sodium bicarbonate and with water, dried overy anhydrous sodium sulfate and the chloroform finally evaporated. The residue crystallized from acetone-hexane, furnishing 16amethyl-A pregnene-3 5,1 :,l7oc-U1i0l-Z0-0116.

The preceding compound was divided into 4 portions of 1 g. each and each portion was treated with acetic anhydride, propionic anhydride, caproic anhydride and cyclopentylpropionic anhydride respectively, in accordance with the methods of Examples IV and V. The ester groups at C-3 and C-11 were selectively hydrolyzed in the 3,1l,l7-.triesterified compound as described in Example IV. Thus the 17-acetate, 17-propionate, 17-ca roate and 17-cyclopentylpropionate, respectively, of 16amethyl-A -pregnene-3fi,11a,17a-triol-20-one were obitained.

' The foregoing compounds were then reacted exactly as described in Example I and thus there were obtained, consecutively: the 17 acetates, l7-propionates, 17-caproates and 17-cyc1opentylpropionates, respectively of 16amethyl 5a,6o-difluoro-pregnane-3fi,lla,l7ot-triol-20-one,

16oumethyl-5a,6oc-difiuoro-pregnanl7oc-O1-3, 1 1,20atrione and of 16a-methyl-6a-fluoro-11-keto-17vt-hydroxyprogesterone.

Example IX To a solution of 10 g. of IGu-methyl-M-pregnene- 318,11u-dio1-20-one diacetate (prepared in accordance with the procedure of Example VIII) in 120 m1. of acetic acid, were added a few drops of acetic acid saturated with dry hydrogen bromide. A solution of 7.4 g. of bromine in 60 m1. of acetic acid was then added slowly while stirring and maintaining the temperature of the reaction mixture at about C. It was then stirred for an additional half an hour, poured into water and the solid was collected by filtration, water washed and dried in vacuo. The resulting 16a methyl 5 a,6fi,17-tribron1o-pregnane- 3B,11a-diol-20 one diacetate was dissolved in 1200 of acetone, 60 g. of sodium iodide were added and the mixture was refluxed for 15 hours. It was then concentrated to small volume under reduced pressure, then poured into water and the product was extracted with ether. The extract was washed consecutively with aqueous 10% sodium sulfite and with water, dried over anhydrous sodium sulfiate and evaporated to dryness below 35. The residue, 16oz methyl 17-bromo-A -pregnene-3fl,1la-diol-ZO- one diacetate was refluxed with 80 ml. of 'y-collidine for 1 hour. The collidine hydrobromide was removed by filtration and washed with ether, the combined solutions were diluted with more ether, washed consecutively with dilute hydrochloric acid and with water, dried over anhydrous sodium sulfate vand evaporated. The residue was crystallized from acetone to afford 16-methyl-A -pregnadiene-3,B,11a-diol-20-one diacetate.

The foregoing compound was dissolved in 700 ml. of ethyl acetate, 5 g. of Raney nickel were added and the mixture was hydrogenated during 2 /2 hours, whereby approximately 1 molecular equivalent of hydrogen was absorbed. Afiter removal of the catalyst by filtration, the solvent was evaporated and the residue crystallized from methanol, thus obtaining 16/8-methyl-M-pregnene-3p,l1adiol-ZO-one diacetate.

A mixture of 9 g. of the above compound and 450 ml. of 1% methanolic potassium hydroxide was kept at 40 for 10 hours under an atmosphere of nitrogen with stirring. The mixture was then neutralized by the addition of acetic acid, concentrated to small volume and, finally, poured into ice-water. The solid was collected by filtration, water-washed, dried and crystallized from acetone-hexane. Thus 16!? methyl A -pregn'ene-3d11adiol-ZO-one were obtained.

8 The foregoing compound was submitted to the reactions described in Example I and thus were obtained, consecutively: 16/8 methyl-5a,6ot-difluoro-pregnane-3fl,1lot-diol- 20-one, 16 fi-rnethyl-S a,6u-difiuoro-pregnane-3, 1 1,20-trio-ne and l6fi-methyl-6a-fluoro-1l-keto-progesterone.

Example X By following the method described in Example IX, 16,8- rnethy1-A -pregnene-3d11a-diol-20-one diacetate was prepared. The 17a-hydroxy group was then introduced, exactly as described for the 17u-hydroxylation of 16a-methyl-A -pregnene-3/3,11u-diol-20-one diacetate in Example VIII. By the concomitant hydrolysis of the acetoxy groups, 16/? methyl-A -pregnene-3 l3,110c,170L-t1'i0120-0D6 was obtained which was then divided into several 1 g. portions and each portion was esterified selectively at C17, as described in Example- VIII, yielding the 17aacetate, 17- propionate, 17-capr-oate and 17-cyclopentylpropionate, respectively of 16fl-methyl-A -pregnene-3B,1lu,l7a-triol-20- one.

By application of the reaction sequence described in Example I, there were obtained, consecutively: the 17- acetates, 17-propionates, 17-caproates and 17-cyclopentylpropionates, respectively, of 16fi-methyl-5a,6ot-difiuoropregame-313,11u,17a-triol-20-one, of 16B-methyl-5a,6adifluoro-pregnan-17otol-3,11,20-trione and of 16,8-methyl- 11-keto-17a-hydroxy progesterone.

Example X I Exactly as described for the inversion of the methyl group of 16ot-methyl-A -pregnene-3,8,11a-diol-2O-one diacetate in Example IX, l6u-rnethyl-A -pregnen-3 8-01-20- one acetate [Marker et al., J. Am. Chem. Soc., 64, 1280 (1942)] was converted to 16/3-methyl-A -pregnen-3 3-01- 20-o-ne. Upon bromination of 16a-methyl-A -pregnen-3B- ol-20-one acetate there was obtained t-II1ethyl-5oc,6fi,17- tribrorno-pregnan-3B-ol-ZO-one acetate; the subsequent treatment with sodium iodide afforded 16ot-methyl-17B- bromo-M-pregnen-3 8-ol-20-one; the following collidine treatment yielded 16-methy1-A -pregnadien-3 3-01-20- one; finally by the hydrogenation, 16p-methyl-A -pregnen- '3 3-ol-20-one acetate was obtained. A conventional alkaline hydrolysis of the 3-acetoxy group afforded the (3-3 alcohol.

By application of the reactions described in Example I, from 16fi-methyl-A -pregnen-3,B-ol-20-one were obtained, consecutively: 16,8 methyl-5a,6a-difluoro-pregnan-3fl-ol- 2O one, 163 methyl-5a,6a-difluoro-pregnane-3,20-dione and l6,8-methyl-6a-fluoro-progesterone.

Example XII In accordance with the esterification procedures described in Examples IV and V, the acetate, propionate, caproate and cyclopentylpropionate, respectively of A pregnene-3B,11a,17u-triol-20-one [Halpern and Djerassi, J. Am. Chem. Soc., 81, 439 (1959)] were prepared and submitted to the reactions described in Example I. Thus were obtained, consecutively: the 17-acetate, 17-propionates, 17-capnoates and 17-cyclopentylpropionates, respectively, of 5a,6u-difluoro-pregnane-3B,11a,17et-triol, of 5a, 6a-difluoropregnan-17u-ol-3,11,20-trione and of ll-keto- 17ot-hydroxy-progesterone. 5a,6a-difluoro-pregnan-17uol-3,11,20-trione was found to inhibit the excretion of the gonadotrophic hormone.

Example XIII 5 g. of A -pregnadiene-3/8Jlu-diol-ZO-one [Halpern and Djenas-si, J. Am. Chem. Soc., 81, 439 (1959)], in 250 ml. of ethanol were shaken in a hydrogen atmosphere, over 1 g. of 5% palladium charcoal catalyst at room temperature and atmospheric pressure, up to the uptake of about 1 equivalent of hydrogen. Removal of the catalyst followed by recrystallization of the residue from acetone- 7 hexane, furnished A -pregnene-3B,11a-diol-20-one. The reactions described in Example I gave consecutively 5 (1,60:-

difluor-o-pregnane-3 [3,1 1a-diol-20-one, 5a,6ot-difluoro-preg- (113116-351 1 ,20atrione and 6u-fluoro-1 l-keto-progesterone.

Example XIV In accordance to the procedure mentioned in the foregoing example, A -pregnadienedfi-ol-l1,20-dione, the product of the side chain degradation of botogenin [Rothman and Wall, J. Am. Chem. Soc, 81, 411 (1959)], was converted to A -pregnen-3/3-ol-11,20-dione acetate, which was saponified in accordance with the method of Example Treatment with lead tetraacetate and hydrogen fluoride, in accordance with the procedure described in Example I, afforded 5a,6a-difluormpregnanflaol-11,20- dione, which was oxidized, also in accordance with the procedure described in Example I, to give 50,6oc-diflLlOT0- .pregnane-3,11,20-trione, identical with the intermediate of Example )GII.

Example XV By the usual treatment with ethyleneglycol in presence of p-toluenesulfonic acid, refluxing in benzene, the 20- cycloethylene'ketal of A -pregnen-3fi-o1-11,20-dione (see Example X) was obtained. By also known methods, by reaction with lithium aluminum hydride and subsequent hydrolysis of theketal group, A -pregnene-3B,11/3-diol-20- one was then obtained; in accordance with the procedure described in Example I, by the reaction with lead tetraacetate and hydrogen fluoride, 5a,6ot-difluono-pregnane- 3,6,11,8-dio1-20-one was'further produced and oxidized to 15a,6ardifluoro-pregnane-3,11,20-trione, identical with the intermediate Example XIII.

Example XVI 4 g. of A -pregnene-3B,11a,17a-triol-20-one [Halpern and Djerassi, J. Am. Chem. Soc., 81, 439 (1959)] was dissolved in 50 ml. of chloroform containing 1 ml. of pyridine, the solution was chilled in a Dry Ice-acetone bath and 1.05 molecular equivalents of chlorine in carbon tetnachloride were added. The temperature of the mixture was allowed to rise to room temperature and then a current of nitrogen was passed through the mixture to remove the excess of chlorine. The solution was then washed consecutively with aqueous 2 N hydrochloric acid, water, aqueous 5% sodium bicarbonate and water, dried over anhydrous sodium sulfate and evaporated. The residue crystallized from methanolebenzene, affording 5ot,6,8-dichloro-pregnane-3 18, 1 1a, l7ot-triol-20-one.

3 g. of the foregoing compound were dissolved in 150 .ml. of dioxane and 1.2 g. of bromine, dissolved in 7 ml. of dioxane was added, slowly, with stirring, maintaining .the temperature below 15 C. After addition of the bromine stirring was continued for further minute-s and then the mixture was poured into aqueous sodium bicarbonate, the product extracted with chloroform, the extract water-washed, dried over anhydrous sodium sulfate and evaporated under reduced pressure. Thus, 50,6B-dichloro 2.1 -bromo pregnane 3fl,110t,17ot.-tfl0 l 20 one was obtained.

To a solution of 3g. of the above compound in 120 ml. of dry acetone, 3.9 g. of anhydrous potassium acetate, 1.8 g. of sodium iodide and 1.5 ml. of glacial acetic acid were added, and the mixture was refluxed for 9 hours. Atthe end of this timeit was poured into water, the product was extracted with chloroform, the extract was washed with water, dried over anhydrous sodium sulfate and evaporated. The residue crystallized from acetonehexane furnishing 5a,6/3-dichloro-pregnane-3B,11a,17a,21- tetrol-20-one 21-acetate.

To a solution of 5 g. of the foregoing compound, in 500 ml. of glacial acetic acid, 5 g. of zinc-dust was added, :little by little, while stirring. The temperature was then -slowly raised to 40 C. and this temperature'maintained in further half an hour with continuous stirring. From :the, cooled mixture the zinc .was removed by filtration, the residue was washed .with acetone, and the cooled solutions 1 .0 .were evaporated to dryness. The residue crystallized-from aqueous methanol, furnishing A -pregnene-3p,1,1a,17x,2,1- tetrol-20-one 21-acetate.

By following the method described in Example I the above compound was converted into 5a,6x-difiuono:pregham-313,11a,17u,2l-tetrol-20-one Zl-acetate.

An ice-cold solution of 5 g. of the foregoing compound in 250 ml. of acetone was treated with an excess of 8 N chromic acid, with stirring. The 8 N chromic acid was prepared in aqueous dilute sulfuric acid. The temperature was maintained at 0 during the addition. Stirring .Was then continued for 2 minutes more, the mixture was poured into ice-water and the solid was collected by filtration, water-washed, dried and crystallized from acetone-hexane. Thus 5u,6u-difiuoro-pregnane 17a,21-diol 3,11,20-trione 21-acetate was obtained.

A mixture of 5 g. of the'fonegoing compound, 5 got sodium acetate and ml. of methanol was refluxed for 2 hours, then cooled, diluted with ice-water up to complete precipitation of the product, which was collected by filtration, water-washed, dried and crystallized from acetonehexane. Thus fioc-flllOIO-COItiSOIlG 2l-acetate was obtained.

Example XVII A -pregnene-3fi,17u,21-tri0l-210-one [Fuchs and Reichstein, Helv. Ch. Acta, 24, 401 (1941 )1 was acetylated selectively at C-2l by treatment with 1.1 molecular equivalent of acetic anhydride in pyridine overnight, and then treated with lead tetraacetate and hydrogen fluoride, following the technique described in Example 1. Thus, 5a,6a-difluoro pregnene-QB,l7a,21-triol-20-one ZI-acetate was obtained, which in turn was oxidized with 8 N chromic acid to 5a,6a-difluoro-pregnane-17a,21-diol-3,20-dione 21-acetate. Subsequent treatment with sodium acetate ,in methanol under reflux gave Ga-fluoro-M-pregnene-17a,21-diol-3,20- dione 2l-acetate. The oxidation step with 8 N chromic acid and the treatment with sodium acetate were effected exactly as described in Example I.

Example XVIII The procedure of Example XVI was repeated with lead dioxide instead of lead tetraacetate, and 5a,-6u-difluoropregnane-Spd1a,17u,2l-tetrol-20 one Zl-acetate was ob tained identical with the product obtained in Example XVI.

Example XIX A suspension of 3 g. of 16a,17a-isopropylidenedioxy- A -pregnene-3fl,21-diol-20-one diacetate (Petrow -et al., J. Chem. Soc, 1955, 4383) in 30 cc. of methanol was cooled to 0 C. and treated under nitrogen atmosphere, with stirring, with 300 mg. of potassium hydroxide dissolvedin 1 cc. of water and 5 cc. of methanol and the mixture stirred at 0 C. for 1 hour. The resulting solution was neutralized with acetic acid, diluted with water and the crystalline compound, 16a,17a-isopropylenedioxy- A -pregnene-3fl,21-diol-20-one collected by filtration, water-washed, dried and then selectively acetylated at 0-21, treating it with 1.1 molecular equivalents of acetic 'anhydride in pyridine at 0 C. and overnight. Conventional isolation techniques yielded 16a,17a-isopropylidenedi0xy A -pregnene-3,B,21 di-ol 20 one 21-acetate. .This compound was then submitted to the lead tetraacetate-hydrogen fluoride treatment, followed by oxidation and finally to sodium-acetate treatment, exactly as described in Ex ampleI. Thus there were obtained consecutively: 50:,6oa-difi11010 16a,17a isopropylidenedioxy pregnanc- 3fi,2l-di-ol-20 -one, 5a,6u-difluoro-l6a,l7a-isopnopylidenedioxy-pregnan-Z1-ol-3,20-dione acetate (which exhibited anti-androgenic activity) and 6a-fluor0-l6a,l7a-isopropyl- 1 l 5a,6a-difluoro-pregnane-16a,17a,21-triol 3,20 dione and 6a-fluoro-A -pregnene-16a,17a,21-triol-3,20 dione. Conventional esterification with acetic anhydride in pyridine solution at room temperature afforded the corresponding 16a,21-diacetate.

Example XX 10 g. of 16a-methyl-A -pregnene-3fi,17a-diol-20-one (Example IV) was dissolved in 50 ml. of methylene chloride. The solution was chilled to 10 C. and 9.6 g. of bromine, dissolved in 24 ml. of methylene chloride was added over a period of 20 minutes, while stirring and maintaining the temperature at C. Water was then added, the organic layer separated, washed with water, dried over anhydrous sodium sulfate and evaporated to dryness, at reduced pressure at an inside temperature of less than 50 C. The residue consisted in the 16a-methyl-5a,6[3,21- tribromo-pregnane-3fi,17a-diol-20-one.

To a solution of the foregoing tribromo compound in 200 ml. of acetone, 40 g. of sodium iodide was added and the mixture was stirred for 15 minutes and then left at room temperature overnight. Water was added, the prodnot was extracted with methylene chloride and the extract was washed consecutively with aqueous 3% sodium thiosulfate and water. It was then dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated at reduced pressure, from a water-bath heated to 40 C. After cooling the precipitate was filtered, water-washed and dried in vacuo affording 16a-methy-l-21-iodo-A -pregnene-BflJh-diol-ZO-one. This compound was refluxed with 45 g. of potassium acetate in 300 ml. of acetone for 14 hours. The mixture was then concentrated to a small volume, cooled, diluted with water and extracted with ether. The extract was Washed with water dried over sodium sulfate and concentrated to small volume. Upon cooling, 16a-methyl-A -pregnene-3fi,17u,21-triol-20 one 21-acetate precipitated in crystalline form and was collected by filtration, water washed and dried.

By the method described in Example I, the above compound was treated with lead tetraacetate and hydrogen fluoride to yield 16a-methyl-5a,6a-difluoro-pregnane-35, 17a,21-triol-20-one 21-acetate. In accordance with said example it was oxidized to 16a-methyl-5adifluoropregnane-17,21-diol-3,20-dione 21-acetate. Finally by refluxing with sodium acetate in methanol (cf. Example I) 16azmethyl-Ga-fluOro-A -pregnene-17a,21-diol-3,20 dione 21- 'acetate was produced.

Example XXI By the method described in Example I, 5 g. of A -preg nene-3{3,17a,21-triol-11,20-dione [Rothman and Wall, I. Am. Chem. Soc, 81, 481 (1959)] was treated with lead tetraacetate and hydrogen fluoride and there was finally obtained 5a,6a-difiuoro-pregnane-3p,l7a,21-triol 11,20- dione.

Following the technique described in Example I, this compound was oxidized to 5a,6ct-difluoro-pregnane-17a, 21-diol-3,11,20-trione, identical with the intermediate obtained in Example XVI.

Example XXII 5 g. of A -pregnene-3fl,17a,21-triol-11,20-dione acetate were hydrolyzed to the free alcohol and the -semicar- 'bazone was then formed. The latter was treated with lithium aluminum hydride, the ZO-keto group was regenerated by known methods and thus A -pregnene-3B,1 16,17a, 2l1-tetrol-20-one was obtained, which was selectively acetylated at C-Zl by reaction with 1 equivalent of acetic anhydride in pyridine at 5 C. during 4 hours. Then the lead tetraacetate-hydrogen fluoride reaction as described in Example I was employed to give 5a,6a-diflu-oro-pregnane- 35,1113,17a,21-tetrol-20-one-21 acetate. Subsequent oxidation with 8 N chromic acid afforded 5 a,6a-difluoro-pregnane-17a,21-diol-3,l1,20-trione ZI-acetate identical with the intermediate of Example XVI.

12 Example XXIII A solution of 5 g. of A -androstene-3B,17,6-diol, in ml. of methylene chloride was added to a mixture of 10 g. of lead tetraacetate and 20 ml. of anhydrous hydrogen fluoride mixture which had been previously chilled to 80, in a Dry Ice-acetone bath. The solution of the steroid was added over 15 minutes with stirring, and was then stirred for additional 15 minutes, at 80 C. At the end of this time the mixture was cautiously poured into an ice-cold solution of sodium carbonate in water, containing an excess of sodium carbonate. The organic phase was separated, the aqueous phase extracted with methylene chloride, the cooled methylene chloride solutions were washed with water to neutrality, dried over anhydrous sodium sulfate and evaporated to dryness. The residue was chromatographed over neutral alumina to afford 5a,6a-difluor'o-androst-ane-fi,8,17fi-diol which exhibited anti-estrogenic activity.

An ice-cold solution of 5 g. of the foregoing compound, in 250 ml. of acetone, was treated with an excess of 8 N chromic acid, with stirring. The 8 N chromic acid was prepared in aqueous dilute sulfuric acid. The temperature was maintained at 0 during the addition. The mixture was then stirred, under the same conditions, for 2 minutes more. At the end of this time it was poured into ice-water, the solid was filtered, washed with Water, dried, and crystallized from acetone-hexane. Thus 5rx,6oc-dlflll oro-androstane-3,17-dione was obtained.

A mixture of 5 g. of the above compound, 5 g. of sodium acetate and ml. of methanol was refluxed for 2 hours; at the end of this time, it was diluted with an excess of water. The product was filtered, washed with water, dried and crystallized from acetone-hexane, afiording 6afluoro-A -.androstene-3, 17-dione.

Example XXIV Exactly as described in Example XXIII, 17a-methyl- A -androstene-3/3,17 8-diol was treated with lead tetraacetate and hydrogen fluoride. 17a-methyl-5a,6a-difluoro-androstene-3fl,l7 3-diol [was produced; the subsequent 8 N chromic acid oxidation yielded 17a-m6l3hyl-5oz,6a.- difluoro-androstan-17,8-01-3-one; finally, by refluxing the foregoing compound with sodium acetate, 17a-met-hyl- 6a-fluoro-testosterone was produced.

Example XXV By the reaction described in Example XXIII, from ethyl-A -androstene-3/3,17fi-diol were produced consecutively: 17a-ethyl 50:,6a difluoro-androstane-3fi,17fl-diol, 17u.-ethyl-5a,6a-difluoro-androstan-l7p ol-3-one and 170:- ethyl-6a-fluoro-testosterone.

Example XXVI By the reactions described in Example XXIII, from 17a.-ethinyl-A -androstene-3B,17fi-diol were produced consecutively: 17a-ethinyl-5a,6a-difluoro-androstane-3B,17;?- diol, and 17a-ethinyl-5a,6a-difluoro-androstan-17 8-01-3- one; both compounds exhibited anti-androgenic activity.

Example XX VII The procedure of Examples XXIII and XXIV was repeated but using lead dioxide instead of lead tetraacetarte to produce the intermediates 5a,6a-difluoro androstane- 35,17B-diol and 17a-methyl-5a,6u-difluoro-androstane- 3,8,17fi-d-iol, respectively.

Example XX VIII 5 g. of 19-nor-A -androstene/3B,17/3-diol [Hartman, I. Am. Chem. Soc., 77, 5151 (1955)] was submitted to the reactions described in Example XXIII. Thus were obtained, consecutively: 5a.,6a-difluoro-19-nor-androstane- 35,17p-diol, 5a.,6a-diflu0r0-19-nor-androstane 3,17-dione and 6a-fluoro-19-nor-A -androstene-3,l7-dione.

Example XXIX 17a-methyl-19-nor A androstene-3[i,17;3-diol [Iriarte et al., J. Am. Chem. Soc. 81, 436 (1959)] was submitted to the reactions described in Example XXIII. Thus there were obtained, consecutively: 17a-methyl-5a,6a-difluoro- 19-nor-androstane-3B,17fl-diol, 17ec-methyl-5u,6a-difluoro- 19-nor-androstan-17fi-ol-3-one and l7a-methyl-6a-fluoro- 19-nor-testosterone.

Example XXX '17a-ethyl l9 nor A -androstene-3 3,17B-diol [Iriarte et aL, J. Am. Chem. Soc., 81, 436 (1959)] was submitted to the reactions described in Example XXIII. Thus there were obtained, consecutively: 17a.-ethyl-5a,6a-difluono-d9-nor-androstane-3fi,17fi-diol, 17a-6thyl-5a,6oc-dlfluoro-l9-nor-androstan-17fi-o1-3-one and 17a-ethyl-6aflu-oro-19-nor-testosterone; these compounds exhibited anabolic activity.

Example XXXI 17u-ethinyl-19-nor-A -androstene 3[3,17fl diol [Iriarte et al., J. Am. Chem. Soc., 81, 436 (1959)] was submitted to the reactions described in Example XXVII. Thus were obtained, consecutively: 17a-ethinyl-5a,6a-*difluoro- 19-nor-androstane-318,17flrdiol, 17a-eth1'nyl-5a,6a.-difluoro- 19-nor-androstan-17B-ol-3-one and 17a-ethinyl-6m-fluoro- 19-nor-testosterone.

Example XXXII The procedure of Example XXXI was repeated but using lead dioxide instead of lead tetraacetate and carbon tetrachloride, instead of methylene chloride to produce the intermediate 17a-ethinyl-5u,6a-difluoro-19-nor-androstatue-3,6, 17,8-diol.

Example XXXIII Example XXXI V 16p-methyl-A pregnen-3fi-ol-20-one acetate described in. Example XI was subjected to the method described in Example VIII for introduction of the hydroxyl group at C-17a. The thus formed 16fi-methyl-A -pregnene-3 6,170- diol-20-one was divided into 5 portions of 1 g. each and submitted to the reactions described in Example VI. Thus there were obtained 5a,6a-difluoro-16B-methylpregnane- 3fi,17a-diol-2=0-one, iafia-difiuoro-16fl-methyl pregnan- 17u-ol-3,20-dione, and 6ot-fluoro-l6p-methyl-17a-hydroxyprogesterone and the 17-acetates, 17-propionates, 17- eaproates, and 17-cyclopentylpropionates respectively of said compounds.

Example XXX V 16a-methyl-A -pregnen-3,8-01-20 one acetate [Marker et al., I. Am. Chem. Soc., 64, 1280 (1942)] was saponified by conventional alkaline hydrolysis to aiford the C-3 alcohol. By applying the reactions described in Example I, there were obtained from 16a-methyl-A -pregnen- 3B-ol-20-one, consecutively: 5,a,'6a.-difluoro-1Got-methylpregnan-3fl-ol-20 one; 6a,6a-difiuoro 16a methyl-pregnane-3,20dione and 6a-fluoro-16a-methyl-progesterone.

I claim:

1. A process for the preparation of 5a,6a-difluoro 14 steroids selected from the group consisting of the following formulas:

wherein R and R are selected from the group consisting of hydrogen and methyl, R and R are selected from the group consisting of hydrogen, hydr-oxyl and a hydrocarbon carboxylic acyloxy group of less than 12 carbon atoms, R R and R are selected from the group consisting of hydrogen and a hydrocarbon carboxylic acyl group of less than 12 carbon atoms, R and R together with the oxygen function represent the grouping.

0 /R7 Ea -0 31 wherein R is selected from the group consisting of hy-- drogen and an aliphatic hydrocarbon radical of less than 8 carbon atoms, Y is selected from the group consisting of hydrogen, keto and B-hydroxyl; Z is selected from the group consisting of keto and ,B-hydroxy, and A is selected from the group consisting of keto OH OH and wherein R represents an aliphatic hydrocarbon radical containing up to 8 carbon atoms, comprising reacting the corresponding A -3pehydroxy compound with anhydrous hydrogen fluoride and a metallic reagent selected from the group consisting of lead tetraacetate, lead dioxide, osmium tetroxide and cobaltic oxide.

2'. The process of claim 1, wherein lead tetraacetate is the metallic reagent.

3. The process of claim 1- wherein lead. dioxide is the metallic reagent.

4. A process for the preparation of 5a,6a-difluoro 1 5 steroids selected from the group consisting of the following formulas:

Eli

CHaR (i= ln z Aw R3 3112011 o=o |--OR$ wherein R and R are selected from the group consisting of hydrogen and methyl, R and R are selected from the group consisting of hydrogen, hydroxyl and a hydrocarbon carboxylic acyloxy :group of less than 12 carbon atoms, R R and R are selected from the group consisting of hydrogen and a hydrocarbon car-boxylic acyl group of less than 12 carbon atoms, R and R together with the oxygen function represent the grouping wherein R is selected from the group consisting of hydrogen and an aliphatic hydrocarbon radical of less than 8 carbon atoms, Y is selected from the group consisting of hydrogen, keto and fl-hydroxyl; Z is selected from the group consisting of keto and B-hydroxyl and A is selected from the group consisting of keto,

OH K and steroids selected from the group consisting of the follow- CHzR znloru olt I -OR wherein R and R are selected from the group consisting of hydrogen and methyl, R and R are selected from the group consisting of hydrogen, hydroxyl and a hydrocarbon car-boxylic acyloxy group of less than 12 carbon atoms, R R and R are selected from the group consisting of hydrogen and a hydrocarbon carboxylic acyl group of less than 12 carbon atoms, R and R together with the oxygen function represent the grouping wherein R is selected from the group consisting of hydrogen and an aliphatic hydrocarbon radical of less than 8 cm'bon atoms, Y is selected from the group consisting of hydrogen, keto and fi-hydroxyl; Z is selected from the group consisting of keto and ,B-hydroxy and A is selected from the group consisting of keto,

OH OH and H R wherein R represents an aliphatic hydrocarbon radicai containing up to 8 carbon atoms, comprising reacting the corresponding A -3B-hydr0xy compound with anhydrous hydrogen fluoride and lead dioxide at a temperature ranging from C. to 10 C. in an inert solvent.

8. A process for the production of a 5a,6a-difluoro androstane of the following formula:

1 7 wherein R is selected from the group consisting of hydrogen and methyl, Z is selected from the group of keto and fl-hydroxy and A is selected from the group consisting of keto,

wherein R represents an aliphatic hydrocarbon radical containing up to 8 carbon atoms, comprising reacting the corresponding A -3fl-hydroxy-androstene with anhydrous hydrogen fluoride and lead tetraacetate in an inert solvent at 80 C. to 1tl C.

9. The process of claim 8 wherein the reaction is effected at 80 C.

10. A compound of the following formula:

Eli]

wherein R is selected from the group consisting of hydrogen and methyl; A is selected from the group consisting of keto and in which R' is selected from the group consisting of hydrogen and an aliphatic hydrocarbon radical of less than 8 carbon atoms; and Z is selected from the group consisting of keto and fl-hydroxy.

1 1. 5a,6a-difluoro-androstane-3/3,17B-diol.

12. 17a ethyl-5u,6a-difluoro-l9-nor-androstan-l7 3-ol- 3-one.

13. 17a ethinyl 5a,6a difluoro-androstan-l75-01-3- one.

14. 5a,6a-difluoro-androstane-3,17-dione.

15. 5a,6o-difluoro pregnane-3,20-dione.

16. 50,6oc difluoro-pregnane-l7u-ol-3,20-dione l7-propionate.

17. 50,6oc difluoro 16oz methyLpregnan-17aol-3,20 dione 17-acetate.

18. 504,600 difluoro pregnan 17a o1 3,11,20-trionc.

19. 504,60: difluoro 165 methyl-pregnane-3fl,11a,17atriol-20-one.

20. 504,6oa difluoro pregnane-l7a,2l-diol-3,l1,20- trione ZI-acetate.

21. A compound of the following formula:

OHEORA R Y To R6 radical of less than 12 carbon atoms, Y is selected from the group consisting of hydrogen, keto and hydroXy and Z is selected from the group consisting of keto and 3- hydroxy.

22. 50:,611 difluoro pregnane-Sfi,l6oc,l7a,21-tetrol-20- one.

23. A compound of the following formula:

CHIIOR wherein R is selected from the group consisting of hydrogen and a hydrocarbon carboxylic acyl radical of less than 12 carbon atoms; R is selected from the group consisting of hydrogen and an aliphatic hydrocarbon of less than eight carbon atoms; Y is selected from the group consisting of hydrogen, keto and hydroxy and Z is selected from the group consisting of keto and B-hydroxy.

24. 50:,60; difluoro 16u,17a isopropylidenedioxypregnan-21-ol-3,20-dione 21-aceta-te.

25. A process for the production of 5a,6a-difluoro pregnane selected from the group consisting of those of the following formulas:

wherein R is selected from the group consisting of hydrogen and methyl; R and R are selected from the group consisting of hydrogen, hydroxyl and a hydrocarbon carboxylic acyloxy group of less than 12 carbon atoms, R R and R are selected from the group consisting of hydrogen and a hydrocarbon carboxylic acyl group of less than 12 carbon atoms, R and R together with the oxygen function represent the grouping wherein R is selected from the group consisting of hydrogen and an aliphatic hydrocarbon radical of less than 8 carbon atoms, Y is selected from the group consisting of hydrogen, keto and B-hydroxyl; Z is selected from the group consisting of keto and IS-hydroxy, comprising reacting the corresponding A -3B-hydroXy-pregnene With anhydrous hydrogen fluoride ,and lead tetraacetate in an' inert solvent at -80 C. to -10 C.

26. The process of claim 25 wherein the reaction is effected at 80 C.

"References Cited in the file of this patent UNITED STATES PATENTS OTHER REFERENCES 10 Cutler et a1.: J. O. (3., vol. 80, Dec. 29, 1959, pages 

1. A PROCESS FOR THE PREPARATION OF 5A,6A-DIFLUORO STERIODS SELECTED FROM THE GROUP CONSISTING OF THE FOLLOWING FORMULAS:
 23. A COMPOUND OF THE FOLLOWING FORMULA: 3-Z,5,6-DI(F-),11-Y,16,17-(-O-C(-R7)2-O-),21-(R4-O-)PREGN-20-ONE 